期刊
CANCER LETTERS
卷 502, 期 -, 页码 180-188出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2020.12.038
关键词
Combinatorial therapy; Radiosensitivity; Radioresistance; Small molecule inhibitor; Preclinical models
类别
资金
- DOE Cesium Irradiator Replacement Program [RFP463974]
- Pathways to Cancer Therapeutics Training Grant [T32CA117846-11A1]
- VA Career Development Award [1IK2BX004360-01A1 VA BLRD]
The study demonstrates that the glutaminase inhibitor, telaglenastat, enhances the sensitivity of head and neck cancer cells to ionizing radiation, leading to an enhanced anti-tumor response.
The efficacy of ionizing radiation (IR) for head and neck cancer squamous cell carcinoma (HNSCC) is limited by poorly understood mechanisms of adaptive radioresistance. Elevated glutaminase gene expression is linked to significantly reduced survival (p < 0.03). The glutaminase inhibitor, telaglenastat (CB-839), has been tested in Phase I/II cancer trials and is well tolerated by patients. This study investigated if telaglenastat enhances the cellular response to IR in HNSCC models. Using three human HNSCC cell lines and two xenograft mouse models, we examined telaglenastat's effects on radiation sensitivity. IR and telaglenastat combinatorial treatment reduced cell survival (p <= 0.05), spheroid size (p <= 0.0001) and tumor growth in CAL-27 xenograft bearing mice relative to vehicle (p <= 0.01), telaglenastat (p <= 0.05) or IR (p <= 0.01) monotherapy. Telaglenastat significantly reduced the Oxygen Consumption Rate/Extracellular Acidification Rate ratio in CAL-27 and HN5 cells in the presence of glucose and glutamine (p <= 0.0001). Telaglenastat increased oxidative stress and DNA damage in irradiated CAL-27 cells. These data suggest that combination treatment with IR and telaglenastat leads to an enhanced anti-tumor response. This pre-clinical data, combined with the established safety of telaglenastat justifies further investigation for the combination in HNSCC patients.
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